Pharmaceutical usefulness of bioactive agents depends upon the ability to position therapeutically-effective quantities of intact agent at the target site in the patient. Delivering intact bioactive agents to target sites can be difficult: In vivo degradation of bioactive agents can occur, as well as absorption/retention of the agent by non-targeted systems. Even if pharmaceutically effective amounts of intact agent can be delivered to the vicinity of the target site, accessing the functional location of the site for the bioactive agent can be challenging, particularly if that location is intracellular. For example, certain polar compounds and many large molecules can not enter cells at all because of their inability to cross target cell membranes. In addition, dilution of the bioactive agent by non-specific binding to non-target sites reduces the amount of bioactive agent available to the target site.
Yet another challenge in the therapeutic delivery of drugs or bioactive agents is limiting the toxicities often associated with therapeutically effective concentrations of drugs or bioactive agents. Delivery to a specific target site can also reduce some toxicity normally associated with the administration of a drug or agent. Even when a drug or bioactive agent has no toxicity associated with it, the “loss” of agent through degradation, removal by non-target organs and other delivery failures can significantly and prohibitively increase the cost of the therapy or decrease the efficacy.
One method used to deliver bioactive agents or drugs to tissues and cells is to encapsulate the bioactive agents or drugs in liposomes. Often, an added advantage to this type of formulation is the reduction of the toxicity associated with certain drugs or bioactive agents. The intracellular targeting possibilities that liposomes provide are especially intriguing. While certain cells are known to engulf liposomes, delivery of most liposomes to a target site is not sufficient to deliver the encapsulated contents to the interior of the cell. Fusogenic liposomes are known that allow the liposome's bilayer to fuse with the cell membrane and thus, deliver the encapsulated bioactive agents or drugs to the cell. However, often these fusogenic liposomes lack stability when incubated in serum. In addition, most fusogenic liposomes have not heretofore been able to be targeted to the specific site where the bioactive agent or drug is required. Efficient liposomal delivery to cells in vivo requires specific targeting and substantial protection from the extracellular environment, particularly serum proteins. Unfortunately, most known targeting and protecting strategies also generate large steric barriers on the surface of the liposomes that limit or prohibit fusogenic delivery of the liposomal contents into the interior of the cell. In addition, known targeting and protecting strategies attach targeting/protecting molecules to the liposome through hydrophobic bonding to the liposome's lipid bilayer. These hydrophobic bonds usually inhibit the function of fusogenic membranes. When the hydrophobic moiety is designed to allow dissociation of the targeting/protecting moiety, its dissociation does not occur specifically at the target site.